Co-ENZYME B12 is well known to be involved in the catalysis of about a dozen enzymatic reactions, this includes the reactions catalyzed by the human enzyme, methyl malonylCoA mutase, a critical step in the metabolism of odd numbered fatty acids in the culprit in the inherited disease methyl malonic aciduria. The long term objective of this research is to understand the detailed mechanism by which the co-enzyme B12- requiring enzymes activate the cobalt-carbon bond homolysis in co- enzyme B12. The specific aims in this project are to test the 4effect of corrin ring flexibility on the cobalt-carbon bond dissociation and to explore ligand substitution reaction in vitamin B12 corrinoids. Vitamin B12 derivatives in which two of the "downwardly" projecting side chains are connected via linkers will be prepared. By changing the linkers, the corrin ring fold angle can be altered. Measurement of the activation parameters for Co-C bond homolysis of such models will allow testing the effect of corrin ring flexibility on the "activation" of co- enzyme B12. A systematic study is also designed to explore (1) ligand substitution in corrinoids, (2) the effect of hydrogen bonding on the mechanism of ligand substitution in acquabalamin by derivatization, (3) of hydrogen bonding on the mechanism of ligand substitution in acquacobalamin by derivatization, (3) cis-effect by selective and strategically placed functional groups in C10 in co-balamin, (4) trans-effect in organocobalamin by kinetic studies of the ligand situation, and (5) the effect of replacing the dimethylbenzoimidazole by imidazole on the ligand substitution.